Central nervous system (CNS) disorders extract an enormous financial and personal toll in the United States. In 2014, it is estimated that Alzheimer's disease (AD) alone will cost $214 billion, making it the most expensive condition in the nation. Despite the large investments made to find a cure for AD, it has proven extremely difficult to develop treatments for it and other CNS conditions. A major contributing factor behind this is that virtually nothing is known about the connectional diagram of the human brain, and even small, well studied regions of the brain lack high quality datasets to establish what is normal and what is pathological. The lack of structural information exists because there are no good methods to image the brain in 3D at high resolution over large extents of tissue. This proposal will remove this barrier by developing an optical imaging device that combines a high speed polarization sensitive optical coherence tomography (PS-OCT) microscope and automated vibratome into the same instrument to produce high fidelity, detailed, 3D images of large volumes of unstained CNS tissue with Nissl and AChE quality. It will take a major step towards providing the first wiring diagram of human brain connectivity. This achievement will have profound impact, both with respect to our understanding of normal human anatomy and function, as well as with our ability to identify and quantify the effects of disorders such as autism and Alzheimer's disease. We have put together a world class of team of experts from TissueVision, Massachusetts General Hospital, and Boston University who are experts in the field of neuroanatomy and optical instrumentation, and who have successful commercialization experience in high throughput histology. They will build on the already impressive preliminary results that have been obtained with an early prototype. To validate the technology, we will demonstrate its utility for drug development by atlasing whole brains in mice models and its usefulness for human brain studies by focusing on the entorhinal cortex, a key region in the progression of Alzheimer's disease. Finally, while our emphasis is on neuroscience, the instrument we will build will impact a range of biomedical areas including cancer, cardiac biology, and pharmaceutical development, thus furthering its commercial appeal.